Negative feedback mechanisms play a role in the physiological regulation of stem and progenitor cells and are important in the development and progression of acute and chronic leukemia, myeloproliferative, and myelodysplastic disorders. We are using in vitro and in vivo approaches to study a cell-free inhibitory activity, leukemia-associated inhibitory activity (LIA), which we have identified as a subpopulation of acidic isoferritins (AIF) that are well characterized iron-binding glycoproteins. The inhibitory activity is inactivated by a monoclonal antibody against AIF. The extremely low concentrations needed for action in vitro on normal Ia-antigen-positive cycling granulocyte-macrophage, erythroid, and multipotential progenitor cells and its derivation from normal Ia-antigen-positive monocytes suggest that it may be physiologically relevant. AIF decreases the number of granulocyte-macrophage progenitor cells per femur and per spleen, and the cycling status of these cells in mice undergoing rebound myelopoiesis after treatment with cytoxan. The increase of acidic isoferritins during leukemia from Ia-antigen-negative non-T, non-B cells with Fc receptors and its lack of suppressive action on granulocyte-macrophage progenitor cells from patients with leukemia (who are HLA-DR(Ia)-antigen-negative) suggest that it may be involved in the pathogenesis and progression of leukemia and other blood disorders. AIF interactions are abnormal in mice infected with the Friend virus complex, and this is associated with loss of Ia-antigens on cells releasing and responding to AIF. AIF has been found in normal mouse bone marrow cells during continuous marrow cultures in vitro, and the release of AIF from human monocytes is restricted genetically by HLA-DR (Ia)-antigens at the level of T lymphocyte-monocyte interactions. T8 cells suppress AIF release from HLA-DR-matched monocytes, and this is mediated by gamma interferon. T4 cells induce AIF release from HLA-DR-matched monocytes, and this is mediated by alpha interferon. AIF-release can also be suppressed and induced, respectively, by iron-saturated lactoferrin and purified myeloid colony stimulating factors. We will define further the mechanisms of production and action of AIF-inhibitory activity in vitro. Normal and leukemic mice will be used to determine action in vivo and the significance of AIF to disease progression. We will explore means to modulate the production and action of acidic isoferritins in vitro and in vivo. (T)